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Bone marrow - nonneoplastic

Normal


Reviewers: Dragos Luca, M.D. (see Reviewers page)
Revised: 15 October 2012, last major update September 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
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● 3-6% of total body weight
● Major organ for hematopoiesis at birth; also primary and secondary lymphoid organ
● Hematopoiesis sites change from axial and radial skeleton in newborns to flat bones of central skeleton by mid-teens
● Pluripotent stem cells develop into myeloid blasts (myeloblasts, monoblasts, erythroblasts and megakaryoblasts) or lymphoblasts
● Cells are in storage pools for 5-7 days, then to blood and then to tissues
● Estimated daily production rates to maintain homeostasis in adults: 50-100 x 109 neutrophils, 150-200 x 109 platelets and 150-200 x 109 erythrocytes
● Cellularity of 90-100% in the first years of life, then adult proportions of ~50% reached over a widely variable time interval
● High M:E ratio during the first 3 days of life, progressive decrease by the third week and adult level (3-4:1) at 1.5-3 years of age
● Lymphocytes predominate in the first 1.5-3 years; relatively numerous eosinophils in the first 3 months
● Iron stores are usually absent during the first year of life (exception - first month can have occasional iron stores), then increase progressively and reach adult levels by 5-6 years of life

Diagrams
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Hematopoietic cell differentiation


Bone vasculature


Normal bone marrow differential in adults

Structure
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● Highly organized meshwork of thin-walled capillary-venous sinuses surrounded by extracellular matrix, encased by cortical bone and traversed by trabecular bone (J Clin Pathol 1992;45:645)
● Nutrient (medullary) artery ramifies through marrow space to supply medullary cavity; its arterioles branch into capillaries that are continuous with thin walled sinusoids (capillary-venous sinuses)
Capillary-venous sinus (CVS, basic bone marrow structural unit): inner endothelial cells and outer adventitial reticular cells (phagocytic, can become lipocytes; also synthesize collagen, laminin, fibronectin and proteoglycans)
● All newly formed mature hematopoietic cells are released into capillary-venous sinus, then pass into the blood: transcellularly (via cytoplasm) for erythrocytes and granulocytes, or via megakaryocyte pseudopod extension and fragmentation for platelets
● Capillary-venous sinus coalesce into venules, then veins, carrying newly formed mature hematopoietic cells to the systemic circulation
● No lymphatic channels
Topographic distribution: myeloid - peritrabecular, erythroid – central, megakaryocytes - associated with sinus walls and lymphocytes - throughout (no lymphoid follicles in infancy)

Microenvironment
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● Also known as “hematopoietic inductive environment”
● Formed by the adventitial (stromal) cells and their products (extracellular matrix proteins, cytokines, inhibitory factors and adhesion molecules)
● Provides support for hematopoietic stem cell renewal and produces factors responsible for osteogenesis
Heterogeneous cell population: fixed fibroblasts, macrophages and adipose cells
Extracellular matrix: collagen, fibronectin, laminin, thrombospondin and proteoglycans

Hematopoietic stem cells (HSC)
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● Cells with multilineage hematopoietic differentiation potential and sustained self-renewal activity
● Detected by their ability to regenerate long-term multilineage hematopoiesis in myeloablated recipients
● Very infrequent in the bone marrow: 0.01-0.05% of mononuclear cells
● Defined via functional rather than morphologic characteristics: ability to undergo self-renewal and produce multilineage progeny
● Express CD34, various cytokine receptors / adhesion molecules / extracellular matrix protein receptors (SCF, bFGF, IL11/3/1/6, GM-CSF, etc.)
● Endothelial cells likely have major role in regulation of trafficking and homing of hematopoietic stem cells within the bone marrow
Immunophenotype: CD34+, Thy1+, c-Kit+, Rhodamine123low, Lin-, CD45RO+, CD38-, flt+ and adhesion molecules
Spectrum of evolution / maturation: hematopoietic stem cells → progenitor cell with multilineage commitment → progenitor cell with single lineage commitment → blast cell → mature cell
Developmental continuum: progressive loss of proliferative capacity and gradual acquisition of specific lineage characteristics

Hematopoietic regulatory factors
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● Cytokines produced by T lymphocytes, the monocyte-macrophage lineage and other bone marrow stromal cells (either inducers or inhibitors)
Stimulatory cytokines (inducers): stem-cell factor (SCF), colony-stimulating factors (CSFs) and various interleukins (IL)
Inhibitory cytokines: tumor necrosis factor-beta (TNF-β), transforming growth factor-alpha (TGF-α) and macrophage inflamatory protein-1alpha (MIP-1α)
● Some factors may be pleiotropic (positive or negative effect): TGF-β

Hematopoietic lineages
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Myeloid-monocytic: predominant in the bone marrow, progeny includes neutrophils (most numerous), eosinophils, basophils, monocytes / macrophages, dendritic cells and mast cells
● Other: erythroid, megakaryocytic, lymphoid, natural killer and osteoclasts

Micro description
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Bone marrow biopsy: arterioles, venules, capillaries, sinusoids, adipose tissue, connective tissue and hematopoietic cells; mitotically active cells are usually paratrabecular and perivascular
Bone marrow aspirate: hematopoietic cells (myeloid, erythroid, megakaryocytic, lymphoid), plasma cells (rare in infants), osteoblasts (most common in infants), osteoclasts, occasional adipocytes, endothelial cells or capillaries

Micro images
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Clot section-various images

Bone marrow biopsy:
   
Normal marrow; CD15 staining of myeloid cells

Normal marrow #1,   #2,   #3

Bone marrow aspirate smear:
           
Normal

Virtual slides
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Aspirate smear

Additional references
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Toxicol Pathol 2006;34:548

End of Bone Marrow - nonneoplastic > Normal


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